Evaluating Kidney Function Decline in Children with Chronic Kidney Disease Using a Multi-Institutional Electronic Health Record Database.

BACKGROUND: The objectives of this study were to use electronic health record data from a US national multicenter pediatric network to identify a large cohort of children with CKD, evaluate CKD progression, and examine clinical risk factors for kidney function decline. METHODS: This retrospective cohort study identified children seen between January 1, 2009, to February 28, 2022. Data were from six pediatric health systems in PEDSnet. We identified children aged 18 months to 18 years who met criteria for CKD: two eGFR values <90 and ≥15 ml/min per 1.73 m2 separated by ≥90 days without an intervening value ≥90. CKD progression was defined as a composite outcome: eGFR <15 ml/min per 1.73 m2, ≥50% eGFR decline, long-term dialysis, or kidney transplant. Subcohorts were defined based on CKD etiology: glomerular, nonglomerular, or malignancy. We assessed the association of hypertension (≥2 visits with hypertension diagnosis code) and proteinuria (≥1 urinalysis with ≥1+ protein) within 2 years of cohort entrance on the composite outcome. RESULTS: Among 7,148,875 children, we identified 11,240 (15.7 per 10,000) with CKD (median age 11 years, 50% female). The median follow-up was 5.1 (interquartile range 2.8-8.3) years, the median initial eGFR was 75.3 (interquartile range 61-83) ml/min per 1.73 m2, 37% had proteinuria, and 35% had hypertension. The following were associated with CKD progression: lower eGFR category (adjusted hazard ratio [aHR] 1.44 [95% confidence interval (95% CI), 1.23 to 1.69], aHR 2.38 [95% CI, 2.02 to 2.79], aHR 5.75 [95% CI, 5.05 to 6.55] for eGFR 45-59 ml/min per 1.73 m2, 30-44 ml/min per 1.73 m2, 15-29 ml/min per 1.73 m2 at cohort entrance, respectively, when compared with eGFR 60-89 ml/min per 1.73 m2), glomerular disease (aHR 2.01 [95% CI, 1.78 to 2.28]), malignancy (aHR 1.79 [95% CI, 1.52 to 2.11]), proteinuria (aHR 2.23 [95% CI, 1.89 to 2.62]), hypertension (aHR 1.49 [95% CI, 1.22 to 1.82]), proteinuria and hypertension together (aHR 3.98 [95% CI, 3.40 to 4.68]), count of complex chronic comorbidities (aHR 1.07 [95% CI, 1.05 to 1.10] per additional comorbid body system), male sex (aHR 1.16 [95% CI, 1.05 to 1.28]), and younger age at cohort entrance (aHR 0.95 [95% CI, 0.94 to 0.96] per year older). CONCLUSIONS: In large-scale real-world data for children with CKD, disease etiology, albuminuria, hypertension, age, male sex, lower eGFR, and greater medical complexity at start of follow-up were associated with more rapid decline in kidney function.

Efficacy and patient opinion of wet-wrap dressings using 0.1% triamcinolone acetonide ointment vs cream in the treatment of pediatric atopic dermatitis: A randomized split-body control study.

BACKGROUND: Wet wraps can be an effective means of improving atopic dermatitis (AD). Little research has been done regarding the comparative efficacy of topical steroid vehicles and patient preference. OBJECTIVE: This study aimed to compare the efficacy of 0.1% triamcinolone acetonide ointment vs cream used with wet wraps in pediatric patients with AD and to explore patient preference/opinion. METHODS: We performed a small, randomized, investigator-blind prospective study of 39 pediatric patients experiencing symmetric, bilateral AD flares. Patients were instructed to apply a topical steroid cream to one extremity and apply the same topical steroid in an ointment vehicle to the other extremity using the wet-wrap technique once or twice daily for 3 to 5 consecutive days. Patients were evaluated at a follow-up visit. RESULTS: Comparison of the change in Investigator's Global Assessment scores disclosed no significant difference between efficacy ratings of cream (mean difference = 0.72) and ointment (mean difference = 0.59) when used with wet wraps (P = 0.22). Although patients found the ointment more difficult to apply, they were more likely to prefer ointments for future prescriptions (P < 0.01). CONCLUSION: Patient preference of corticosteroid vehicle is what should ultimately drive treatment. In this small study, we found no difference in efficacy between triamcinolone acetonide wet wraps with cream vs ointment. Dermatologists should select the vehicle of the patient's choice as it may increase satisfaction with treatment.

Association Between Delusions of Infestation and Prescribed Narcotic and Stimulant Use.

OBJECTIVE: Patients diagnosed with delusions of infestation (DOI) at a psychodermatology clinic appeared to have a higher incidence of being prescribed narcotic or stimulant medications compared with the general dermatologic clinic population with chronic pruritic conditions. A retrospective study was conducted examining the correlation between patients with DOI and prescribed psychoactive medications. METHODS: Ninety-two patients with a diagnosis of DOI, seen at our University Psychodermatology Clinic, served as the study population. The comparison group (N=354) included dermatology patients seen at a dermatology clinic by the same dermatologist for itching, including adults seen for chronic pruritic conditions and contact dermatitis. For both groups, the reported use of any psychoactive prescription medications was noted. RESULTS: Patients with DOI were significantly more likely than other dermatology patients to receive prescriptions for narcotics [adjusted odds ratio (OR)=2.19; confidence interval (CI)=1.21-3.99) and stimulants (OR=5.44; CI=2.37-12.52). Patients with DOI were also more likely to be female (OR=2.49; CI=1.47-4.22) than patients who did not have such delusions. DISCUSSION: Few data are available concerning the etiology and management of DOI. Findings from this study indicated an association between the diagnosis of DOI and the prescribing of narcotics and stimulants, even when sex and age were taken into account. This information may be used to assist with the diagnosis of patients presenting with DOI and possible treatment options. It will be important to determine if these medications are a cause of the condition, or are merely correlated with other medical conditions.

Emergence of the primary pediatric stroke center: impact of the thrombolysis in pediatric stroke trial.

BACKGROUND AND PURPOSE: In adult stroke, the advent of thrombolytic therapy led to the development of primary stroke centers capable to diagnose and treat patients with acute stroke rapidly. We describe the development of primary pediatric stroke centers through preparation of participating centers in the Thrombolysis in Pediatric Stroke (TIPS) trial. METHODS: We collected data from the 17 enrolling TIPS centers regarding the process of becoming an acute pediatric stroke center with capability to diagnose, evaluate, and treat pediatric stroke rapidly, including use of thrombolytic therapy. RESULTS: Before 2004, <25% of TIPS sites had continuous 24-hour availability of acute stroke teams, MRI capability, or stroke order sets, despite significant pediatric stroke expertise. After TIPS preparation, >80% of sites now have these systems in place, and all sites reported increased readiness to treat a child with acute stroke. Use of a 1- to 10-Likert scale on which 10 represented complete readiness, median center readiness increased from 6.2 before site preparation to 8.7 at the time of site activation (P≤0.001). CONCLUSIONS: Before preparing for TIPS, centers interested in pediatric stroke had not developed systematic strategies to diagnose and treat acute pediatric stroke. TIPS trial preparation has resulted in establishment of pediatric acute stroke centers with clinical and system preparedness for evaluation and care of children with acute stroke, including use of a standardized protocol for evaluation and treatment of acute arterial stroke in children that includes use of intravenous tissue-type plasminogen activator. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01591096.

Epigenetic analysis of neurocognitive development at 1 year of age in a community-based pregnancy cohort.

Multiple studies show that molecular genetic changes and epigenetic modifications affect the risk of cognitive disability or impairment. However, the role of epigenetic variation in cognitive development of neurotypical young children remains largely unknown. Using data from a prospective, community-based study of mother-infant pairs, we investigated the association of DNA methylation patterns in neonatal umbilical cord blood with cognitive and language development at 1 year of age. No CpG loci achieved genome-wide significance, although a small number of weakly suggestive associations with Bayley-III Receptive Communication scales were noted. While umbilical cord blood is a convenient resource for genetic analyses of birth outcomes, our results do not provide conclusive evidence that its use for DNA methylation profiling yields epigenetic markers that are directly related to postnatal neurocognitive outcomes at 1 year of age.

Extended-release antiepileptic drugs: a comparison of pharmacokinetic parameters relative to original immediate-release formulations.

Many antiepileptic drugs (AEDs) have short half-lives with large fluctuations in peak-to-trough plasma concentrations. Consequences of these pharmacokinetic (PK) properties may include adverse events (AEs) and breakthrough seizures, potentially leading to poor adherence. To address these challenges, newer formulations of these AEDs have been developed using unique extended-release (ER) technologies. These technologies extend the dosing interval such that dosing frequency can be minimized, which may improve patient adherence. Available ER formulations have the potential to minimize the spikes in maximum plasma concentrations (C(max) ) at steady-state that often contribute to AEs during treatment with immediate-release (IR) products. In so doing, tolerability advantages may lead to increased AED effectiveness by improving adherence and allowing higher doses if clinically indicated. Direct PK comparison studies of IR and ER formulations (e.g., carbamazepine, divalproate sodium, lamotrigine, oxcarbazepine, levetiracetam, and phenytoin) have found that dose-normalized ER formulations may or may not be bioequivalent to their IR counterparts, but most ER formulations have a lower fluctuation index ([C(max) -C(min) ]/C(avg) ) compared with the IR versions. This results in flatter concentration-time plots. Not all ER preparations improve the various PK parameters to the same extent, and PK nuances may impact the effectiveness, tolerability, and adherence rates of various ER formulations.

Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes: Report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including antiepileptic drug (AED) teratogenicity and adverse perinatal outcomes. It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine (CBZ), and possibly compared to phenytoin (PHT) or lamotrigine (LTG). It is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. AED polytherapy probably contributes to the development of MCMs and reduced cognitive outcomes compared to monotherapy. Intrauterine exposure to VPA monotherapy probably reduces cognitive outcomes and monotherapy exposure to PHT or phenobarbital (PB) possibly reduces cognitive outcomes. Neonates of WWE taking AEDs probably have an increased risk of being small for gestational age and possibly have an increased risk of a 1-minute Apgar score of <7. If possible, avoidance of VPA and AED polytherapy during the first trimester of pregnancy should be considered to decrease the risk of MCMs. If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered and avoidance of PHT and PB throughout pregnancy may be considered to prevent reduced cognitive outcomes.

Management issues for women with epilepsy--focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid and prenatal vitamin K use and the clinical implications of placental and breast-milk transfer of antiepileptic drugs (AEDs). The committee evaluated the available evidence based on a structured literature review and classification of relevant articles. Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in clinically important amounts. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentrations of lamotrigine, phenytoin, and, to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative (MHD). Supplementing WWE with at least 0.4 mg of folic acid before pregnancy may be considered. Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered, and monitoring of levetiracetam and oxcarbazepine (as MHD) levels may be considered. A paucity of evidence limited the strength of many recommendations.

Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): I. Obstetrical complications and change in seizure frequency: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including the risk of pregnancy complications or other medical problems during pregnancy, change in seizure frequency, the risk of status epilepticus, and the rate of remaining seizure-free during pregnancy. The committee evaluated the available evidence according to a structured literature review and classification of relevant articles. For WWE who are taking antiepileptic drugs (AEDs), there is probably no substantially increased risk (>2 times expected) of cesarean delivery or late pregnancy bleeding, and probably no moderately increased risk (>1.5 times expected) of premature contractions or premature labor and delivery. There is possibly a substantially increased risk of premature contractions and premature labor and delivery during pregnancy for WWE who smoke. WWE should be counseled that seizure freedom for at least 9 months prior to pregnancy is probably associated with a high likelihood (84-92%) of remaining seizure-free during pregnancy. WWE who smoke should be counseled that they possibly have a substantially increased risk of premature contractions and premature labor and delivery.

Adolescent and caregiver experiences with epilepsy.

Epilepsy during adolescence can impede the development of psychosocial independence and typical biological maturational processes. We examined in parallel the experiences and perceptions of adolescent patients with epilepsy and their caregivers. Specifically, we focused on frequency and type of seizures, comorbid conditions, adherence to therapies, productivity, clinical and quality of life consequences of seizures, estimated use and content of seizure emergency plans, and the patient-physician relationship. Two cross-sectional online surveys were conducted among 153 adolescent patients with epilepsy and their respective caregivers. A total of 35% of adolescents indicated that they had been nonadherent to antiepileptic medications in the prior month. Adolescents scored significantly lower compared with their peers on quality-of-life measures. Adolescents and caregivers reported similarly on nearly all domains. An adolescent-centered epilepsy management program may help alleviate concerns and also help the adolescent independently manage their epilepsy as they transition into adulthood.

Rapid infusion of a loading dose of intravenous levetiracetam with minimal dilution: a safety study.

Intravenous antiepileptic drugs are required in patients needing urgent treatment or unable to take oral medication. The safety of intravenous levetiracetam has been established in prospective studies of adult epilepsy and healthy participants. The authors performed a prospective, single-center study to evaluate the safety of a rapid loading dose of intravenous levetiracetam. Patients were divided into 3 equal dosing groups (N = 15 each): 20, 40, and 60 mg/kg (corresponding to maximum doses of 1, 2, and 3 g). Electrocardiogram and safety assessment were performed during the infusion. Ages were 4 to 32 years. Postinfusion serum levetiracetam concentrations were 14 to 189 microg/mL. There were no significant changes in blood pressure, no local infusion site reactions, and no electrocardiogram abnormalities. The authors concluded that high serum levels of parenteral levetiracetam can be achieved rapidly and safely, in a small infusion volume. This finding has important implications for the treatment of status epilepticus.

Thrombolysis in acute childhood stroke: design and challenges of the thrombolysis in pediatric stroke clinical trial.

BACKGROUND: Although tissue plasminogen activator (tPA) has revolutionized the treatment of acute ischemic stroke in adults, no thrombolysis trials in childhood stroke have been conducted. Experience in adults cannot be applied to children due to fundamental age-related differences in coagulation systems, stroke pathophysiology and neuropharmacology. Obstacles to acute treatment trials in childhood stroke include delays in diagnosis and minimizing risk in a vulnerable population. STUDY DESIGN: Thrombolysis in Pediatric Stroke (TIPS) is an international multicenter study to assess the safety of intravenous tPA within 0-3 h and intra-arterial tPA within 3-6 h of onset of arterial ischemic stroke in childhood. Through the International Pediatric Stroke Study, 30 international centers will enroll a total of 48 patients: 24 will be treated with intravenous tPA (0.6, 0.75, 0.9, and 1.0 mg/kg) using the classical dose-finding method, and 24 will be treated with intra-arterial tPA (maximum 0.2, 0.3, 0.4, and 0.5 mg/kg) using a Bayesian dose-finding method. CONCLUSION: The TIPS trial will be the first clinical trial exploring the safety and feasibility of systemic and local thrombolytic therapy in childhood stroke and the obstacles in conducting such a trial.

Antiepileptic drug therapy in pregnancy I: gestation-induced effects on AED pharmacokinetics.

The ideal management of women with epilepsy during pregnancy involves achieving an optimal balance between minimizing fetal exposure to the deleterious influences of both antiepileptic drugs (AEDs) and of seizures. Women with increased seizures during pregnancy tend to have subtherapeutic AED concentrations. Multiple physiological changes during pregnancy influence drug disposition, including increased volume of distribution, increased renal elimination, altered hepatic enzyme activity, and a decline in plasma protein concentrations. Many of the AEDs are characterized by significant increases in clearance during pregnancy. Studies performed thus far provide convincing findings for significant increases in the clearance of lamotrigine and phenytoin during pregnancy; other studies support that phenobarbital, oxcarbazepine, and levetiracetam clearances also most likely increase during pregnancy. Therapeutic drug monitoring of lamotrigine with adjustment of dosages during pregnancy to maintain that individual's target concentration has been shown to decrease the risk for increased seizure frequency. Reports of seizure worsening with decreased concentrations of other AEDs have been reported but not studied in similar formal protocols. Future studies of formal pharmacokinetic modeling of AEDs during pregnancy, with assessment of maternal and fetal/newborn consequences, could provide an important step toward achieving effective drug dosing to maintain therapeutic objectives for the mother but at the same time minimize fetal drug exposure.

Antiepileptic drug therapy in pregnancy II: fetal and neonatal exposure.

The issue of how much an antiepileptic drug (AED) crosses the placenta and relative safety of lactation in mothers receiving AEDs are common clinical questions. Educating potential mothers with epilepsy regarding available information is warranted so that informed decisions and any needed neonatal monitoring is performed. Unfortunately, there is still limited data regarding the degree in which anticonvulsants cross the placenta and penetrate into breast milk. There is a greater appreciation of the factors that influence AED passive transfer across the placenta and into breast milk, as well as factors that ultimately influence neonatal AED distribution. In general, women with epilepsy can have healthy babies even with significant placental exposure and can breast-feed their babies safely with some cautions. Phenobarbital and primidone should be avoided in parents wishing to breast-feed. For the AEDs ethosuximide, levetiracetam, lamotrigine, topiramate, and zonisamide, there is a potential for significant breast milk concentrations; however, there are no firm guidelines on whether lactation is safe. In all cases, parents should be counseled to monitor their child for side effects and the need for routine monitoring.

Practical model-based dose finding in early-phase clinical trials: optimizing tissue plasminogen activator dose for treatment of ischemic stroke in children.

BACKGROUND AND PURPOSE: A safe and effective tissue plasminogen activator (tPA) dose for childhood stroke has not been established. This article describes a Bayesian outcome-adaptive method for determining the best dose of an experimental agent and explains how this method was used to design a dose-finding trial for tPA in childhood. METHODS: The method assigns doses to successive cohorts of patients on the basis of each dose's desirability, quantified in terms of the tradeoff between efficacy and toxicity. The tradeoff function is constructed from several pairs of equally desirable (efficacy, toxicity) probabilities specified by the physicians planning the trial. Each cohort's dose is chosen adaptively, based on dose-outcome data from the patients treated previously in the trial, to optimize the efficacy-toxicity tradeoff. Application of the method to design the tPA trial is described, including a computer simulation study to establish design properties. A hypothetical cohort-by-cohort example is given to illustrate how the method works during trial conduct. RESULTS: Because only a dose that is both safe and efficacious may be selected and the method combines phase I and phase II by integrating efficacy and toxicity to choose doses, it avoids the more time-consuming and expensive conventional approach of conducting a phase I trial based on toxicity alone followed by a phase II trial based on efficacy alone. This is especially useful in settings with low accrual rates, such as trials of tPA for pediatric acute ischemic stroke.

Seizure emergency plans: patient results from a cross-sectional epilepsy survey.

Guidance for seizure emergency plans exists, although their impact and extent of use in patients with epilepsy are undetermined. This study's primary purpose was to measure the estimated use and content of seizure emergency plans. Secondary objectives included measuring: disease severity, quality of life, productivity, and adherence among patients with and without a plan. An online survey was conducted among 408 patients with epilepsy (ages 18-64) who took one or more antiepileptic drugs. Only 30% of patients reported having a plan, which included avoiding injury, notifying a physician, resting/relaxing, and seeking emergency assistance. Those with a plan were more likely to have experienced more seizures in the past year, to have missed school/work, to have incurred injury, to have visited the ER, to have been hospitalized, to fear additional seizures, and to have lost a job. Seizure emergency plans appear to be reserved for adults with more severe disease, but there may be clinical benefits to developing a plan for all adult patients with epilepsy.

Association of non-adherence to antiepileptic drugs and seizures, quality of life, and productivity: survey of patients with epilepsy and physicians.

Non-adherence to epilepsy medications can interfere with treatment and may adversely affect clinical outcomes, although few studies have examined this relationship. This study assessed barriers and drivers to adherence, its impact on quality of life, and the importance of the patient-physician relationship to adherence. Two cross-sectional online surveys were conducted among 408 adult patients with epilepsy and 175 neurologists who treat epilepsy patients. Twenty-nine percent of patients self-reported being non-adherent to antiepileptic medications in the prior month. Non-adherence was found to be associated with reduced seizure control, lowered quality of life, decreased productivity, seizure-related job loss, and seizure-related motor vehicle accidents. Patient-oriented epilepsy treatment programs and clear communication strategies to promote self-management and patients' understanding of epilepsy are essential to maximizing treatment and quality of life outcomes while also minimizing economic costs.

Valrocemide (Teva/Acorda).

Valrocemide is an anticonvulsant agent under development by Teva and Acorda as a potential therapeutic for the treatment of epilepsy. In October 2003, a phase II trial using valrocemide as an adjunct therapy in refractory epilepsy patients had been completed and phase III trials were being planned. Valrocemide was also being investigated for potential utility in the treatment of bipolar disorder and neuropathic pain.